2-Substituted benzimidazole compounds

ABSTRACT

2-Substituted benzimidazole compounds of the formula:  &lt;IMAGE&gt; (I)or, +TR  &lt;IMAGE&gt; (II)  wherein R1 is hydrogen, halogen, lower alkyl or lower alkoxy, and R2 is hydrogen or lower alkyl with the proviso that R1 and R2 do not stand for hydrogen simultaneously and, when R1 is hydrogen, R2 cannot mean a methyl group at 6th position on the pyridin-2-yl group or methyl an isobutyl group on the phenyl group; are useful as anti-inflammatory agents and/or analgesics.

This is a division of application Ser. No. 856,969, filed Dec. 2, 1977.

This invention relates to certain 2-substituted benzimidazole compounds,and to process for their preparation.

The compounds of this invention can be represented by the followinggeneral formula: ##STR2## wherein R₁ is hydrogen, halogen, lower alkylor lower alkoxy, and R₂ is hydrogen or lower alkyl with the proviso thatR₁ and R₂ do not stand for hydrogen simultaneously and, when R₁ ishydrogen, R₂ cannot mean a methyl group at 6th position on thepyridin-2-yl group or an isobutyl group on the phenyl group.

The terms "lower alkyl" and "lower alkoxy" used herein mean those of C₁to C₄.

The compounds of this invention are pharmceutically active agents. Theyare useful as anti-inflammatory agents and/or analgesics.

These compounds of Formula I can be conveniently prepared by reacting acompound of the formula ##STR3## in which R₁ is as defined thereto inFormulae I, or an acid-addition salt thereof with a compound of theformula: ##STR4## wherein R₂ is as defined thereto in Formula I, in thepresence of a condensation agent preferably under a current of nitrogengas. Examples of preferred condensation agents include polyphosphoricacid, polyphosphoric esters, hydrochloric acid, hydrobromic acid andboric acid. The reaction may be carried out, if desired, in an inertsolvents such as O-dichlorobenzene, nitrobenzene or diglyme.Polyphosphoric acid and its esters are most preferable for this reactionbecause they give the compounds I in a higher yield by simply dilutingthe reaction mixture with water and neutralizing.

The starting O-phenylene diaminers III, particularly those having anelectron releasing group are unstable and would encounter difficultiesin handling thereof. These difficulties may be overcome by using theirstable acid-addition salts in the reaction for the synthesis of thebenzimidazole compounds I having an electron releasing group on thebenzene ring.

Alternatively the compounds of Formula I may be prepared by reacting thestarting compound III with a cyanopyridine of the formula: ##STR5##wherein R₂ is as defined in Formula I, in a polar solvent firstly underbasic conditions and then under weakly acidic conditions. Examples ofpreferred polar solvents include dimethylformamide, dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoramide, dimethylsulfoxide,methanol, ethanol and the like. Examples of bases which may be used inthe above reaction include alkali metal alkoxide such as sodiummethoxide, sodium ethoxide or potassium t-butoxide.

Examples of weak acids which may be used in the above reaction includeacetic acid, citric acid, oxalic acid or carbonic acid. The reaction maybe preferably carried out by heating the reactants III and V in a polarsolvent in the presence of a base at the boiling temperature of thesolvent for 15 minutes to several hours, adding a weak acid to thereaction mixture to make the mixture weakly acidic and continuing thereaction at a temperature from 60° C. to the boiling point of thesolvent.

The benzimidazole compounds of the formula: ##STR6## wherein R₁ and R₂are as defined in Formula I, may be advantageously prepared by reactingthe starting compound III with α-picoline or its alkylated derivative ofthe formula: ##STR7## wherein R₂ is as defined, in the presence ofsulfur. This reaction is advantageous in that easily availableα-picoline or its derivatives may be used as such. The reaction may beperformed either without using any solvent or in an inert solvent suchas O-dichlorobenzene or diglyme. Usally 1 to 1.5 moles of the compoundVI and 1.5 to 3 moles of sulfur are used for one mole of the startingcompound III.

The compounds of Formula II can be prepared by reacting the compound ofFormula III or its acid-addition salt with a compound of the formula:##STR8## wherein R₂ is as defined, in the presence of a condensationagent preferably under a current of nitrogen gas. Examples of preferredcondensation agents include polyphosphic acid, its esters, hydrochloricacid, hydrobromic acid and boric acid. The reaction may be carried out,if desired, in an inert solvent such as O-dichlorobenzene, nitrobenzeneor diglyme. Polyphosphoric acid and its esters are most preferablebecause they give the compound II in a higher yield by simply dilutingthe reaction mixture with water and neutralizing.

The compounds of Formula II may also be prepared by reacting thestarting compound III with a compound of the formula: ##STR9## whereinR₂ is as defined, and Y is --CN, --CSSH, --CHO or COOR wherein R is C₁-C₄ alkyl, in a polar solvent firstly under basic conditions and thenweakly acidic conditions. Examples of preferred polar solvents includedimethylformamide, dimethylacetamide, N-methylpyrrolidone,hexamethylphosphoramide, dimethylsulfoxide, methanol, ethanol and thelike. Examples of bases which may be used in the above reaction includealkali metal alkoxide such as sodium methoxide, sodium ethoxide, orpotassium t-butoxide. Examples of acids which may be used in the abovereaction include acetic acid, citric acid, oxalic acid, carbonic acid,hydrochloric acid or hydrobromic acid, and acetic acid is mostpreferable. The reaction may be preferably carried out by heating thereactants III and VIII in a polar solvent in the presence of a base at atemperature from room temperature to the boiling point of the solvent,adding an acid to the reaction mixture to make the mixture weakly acidicand continuing the reaction at a temperature from 60° C. to the boilingpoint of the solvent.

Alternatively the compounds of Formula II may be prepared via a compoundof the formula: ##STR10## wherein R₁ and R₂ are as defined thereto inFormula II.

The intermediate compounds IX may be conveniently prepared by reacting acompound of the formula: ##STR11## wherein R₁ is as defined, with acompound of the formula: ##STR12## wherein R₂ is as defined, in thepresence of aluminum chloride as a catalyst in an inert solvent such asmono - or dichlorobenzene or tetrachloroethane at an elevatedtemperature from 100° to 200° C.

Another route for the synthesis of the compounds IX comprises the stepsof reacting the compound XI with anhydrous methanol or ethanol underacidic conditions to give a compound of the formula: ##STR13## whereinR₂ is as defined and R₃ is methyl or ethyl, and reacting the resultingcompound XII with the compound X in a solvent to give the compound IX.This route is advantageous when the aniline compound X has an electronreleasing group and hence is reactive.

The resulting amidine compounds IX may be then cyclized by reacting witha halogenating agent in an aqueous medium under acidic conditions andthen treating the resulting compound with an alkali under heating.Examples of preferred aqueous medium include mixtures of water with awater-miscible organic solvent such as methanol, ethanol,dimethylsulfoxide or dioxan. Examples of preferred halogenating agentinclude hypochlorites, t-butylhypochlorite and the like. Thehalogenation reaction is conveniently carried out in the presence of anacid such as hydrochloric acid under cooling with ice or at roomtemperature. The resulting N-haloamidine compounds may be isolated fromthe reaction mixture by the extraction with a solvent thereof such asmethylene chloride and subjected to the cylizing reaction. The reactionmixture containing the N-haloamidines may be used as such.

Examples of preferred alkali include sodium carbonate, potassiumcarbonate, sodium hydroxide and potassium hydroxide.

The compounds of this invention have useful pharmacological effects. Toillustrate the anti-inflammatory activity of these compounds, thecompounds indicated in the following table were administered orally at adose of 100 mg/kg to male Wistar rats weighing 110 to 130 g. Edema wasinduced on the foot of animals inaccordance with the method described in"Proceedings of the Society for Experimental Biology and Medicine" 111,544 (1962).

Percents of inhibition of edema after 3 hours were determined.

The data obtained are shown in the following table.

                  Table I                                                         ______________________________________                                                                    %                                                 Compound                    Inhibition                                        ______________________________________                                        2-(5-ethylpyridin-2-yl)benzimidazole                                                                      50                                                2-(6-ethylpyridin-2-yl)benzimidazole                                                                      42                                                2-(6-methylpyridin-2-yl)-5(6)-methylbenzimidazole                                                         48                                                2-(6-methylpyridin-2-yl)-5(6)-methoxybenzimidazole                                                        60                                                2-(6-methylpyridin-2-yl)-5(6)-chlorobenzimidazole                                                         65                                                2-(p-ter-butylphenyl)benzimidazole                                                                        44                                                2-(p-ethylphenyl)benzimidazole                                                                            58                                                2-(p-ethylphenyl)-5(6)-methoxybenzimidazole                                                               88                                                2-(o-ethylphenyl)-5(6)-methoxybenzimidazole                                                               70                                                2-(m-ethylphenyl)benzimidazole                                                                            56                                                phenylbutazone              43                                                ______________________________________                                    

As indicated in the foregoing table, the compounds of this inventionsignificantly exceeded the well known anti-inflammatory agentphenylbutazone.

The compounds of the invention may be used in warm-blooded animals,particularly mammals, as medicaments in the form of pharmaceuticalcompositions containing the compounds in admixture or conjunction with apharmaceutical organic or inorganic, solid or liquid carrier for oral,rectal, or parenteral administration.

The total daily doses can vary from about 1 mg./kg. to about 10 mg./kg.

The preferred route of administration is the oral route. Suitablecompositions include, without limitation, tablets, capsules, powders,solutions, suspensions, sustained release formulations and the like.

To produce dosage units for peroral application, the compositions ofthis invention may be combined, e.g., with solid pharmaceuticallyacceptable pulverulent carriers such as lactose, saccharose, sorbitol,mannitol; starches such as potato starch, corn starch or amylopectin,also laminaria powder or citrus pulp powder, cellulose derivatives orgelatin, also lubricants such as magnesium or calcium stearate orpolyethylene glycols of suitable molecular weights may be added, to formtablets or press coated tablets. The latter are coated for example, withconcentrated sugar solutions which can contain e.g., gumarabic talcumand/or titanium dioxide, or they are coated with lacquer dissolved ineasily volatile organic solvents or a mixture of organic solvents.

Dyestuffs can be added to these coatings, for example, to distinguishbetween different contents of active substances.

Hard gelatin capsules contain, for example, granulates of the instantcomposition with solid pulverulent carriers such as, e.g., lactose,saccharose, sorbitol, mannitol and further starches such as potatostarch, corn starch or amylopectin, cellulose derivatives or gelatin, aswell as magnesium stearate or stearic acid.

Suppositories containing a compound of the present invention are readilyobtained by techniques well known to those skilled in the art ofcompounding dosage forms. A compound of the present invention isdispersed in a carrier such as cocoa butter and the suppositories formedin the usual way.

The compounds of this invention and their preparation are more fullyillustrated by the following examples. These examples are included herefor the purpose of illustration and are not intended as a limitation.

EXAMPLE 1 Preparation of 2-(5-methylpyridin-2-yl)benzimidazole

6.2 g. of o-phenylenediamine, 7.1 g. of 5-methylpicolinic acid and 40 g.of polyphosphoric acid were stirred under nitrogen gas current at 160°C. to 180° C. for 4 hours. To the reaction mixture were added 400 ml. ofwater and then a concentrated aqueous solution of sodium carbonate toneutrality. The resulting crystals were filtered off, dried andrecrystallized from acetonitrile or ethyl acetate to obtain 9.4 g. ofcolorless needles of the product (86% of theory), M.P. 229.0°-229.5° C.

EXAMPLE 2 Preparation of 2-(2-methylpyridin-5-yl) benzimidazole

11.9 g. of o-phenylenediamine, 13.7 g. of 2-methylpyridine-5-carboxylicacid and 100 g. of polyphosphoric acid were stirred under nitrogen gascurrent at 180° C. to 200° C. for 4 hours. To the reaction mixture wereadded 800 ml. of water and then a concentrated aqueous solution ofsodium carbonate to neutrality. The resulting crystals were filteredoff, dried and recrystallized from acetonitrile to give 15.7 g. ofcolorless needles of the product (75% of theory), M.P. 265.5°-266.0° C.

EXAMPLE 3 Preparation of 2-(3-methylpyridin-2-yl)benzimidazole

15.0 g. of o-phenylenediamine, 15.0 g. of 2,3-lutidine and 13.5 g. ofsulfur powder were heated at 160°-170° C. for 8 hours.

To the reaction mixture was added 200 ml. of methanol. The mixture wasfiltered to remove sulfur powder and evaporated in vacuo to remove thesolvent. The residue was subjected to silica gel column chromatographyand recrystallized from cyclohexane.

22.6 g. of colorless needles of the product (77% of theory) wasobtained. M.P. 159.5°-160° C.

EXAMPLE 4 Preparation of 2-(2-methylpyridin-4-yl) benzimidazole

3.4 g. of o-phenylenediamine, 4.4 g. of 2-methylisonicotinic acid and 30g. of polyphosphoric acid were heated at 190°-200° C. under nitrogen gascurrent for 4 hours with stirring.

The reaction mixture was diluted with 500 ml. of water and thenneutralized with sodium carbonate. The resulting crystals were filteredoff, dried and recrystallized from ethyl acetate to give 5.5 g. ofcolorless needles of the product (82% of theory). M.P. 205°-206° C.

EXAMPLE 5 Preparation of 2-(5-ethylpyridin-2-yl) benzimidazol

11.3 g. of o-phenylenediamine, 15.1 g. of 5-ethylpicolinic acid and 80g. of polyphosphoric acid were heated at 180°-190° C. under nitrogen gascurrent for 3 hours with stirring. The reaction mixture was diluted with1,000 ml. of water and then neutralized with sodium carbonate. Theresulting crystals were filtered off, dried and recrystallized fromethyl acetate to give 17.1 g. of colorless needles of the product (78%of theory). M.P. 172.5°-173.° C.

Analysis calculated for C₁₄ H₁₃ N₃ : C, 75.31; H, 5.87; N, 18.82. Found:C, 75.51; H, 5.75; N, 18.68.

EXAMPLE 6 Preparation of 2-(5-ethylpyridin-2-yl)benzimidazole

130 g. of o-phenylenediamine, 121 g. of 5-ethyl-2-methylpyridine and 96g. of sulfur were heated at 160°-170° C. for 20 hours. The reactionmixture was dissolved in 2,000 ml. of chloroform and the solution waswashed with water and 6 N hydrochloric acid successively. Chloroform wasremoved by evaporation in vacuo. The residue was subjected to silica gelcolumn chromatography and recrystallized from ethyl acetate. The productshowed no melting point depression upon mixing with the product of thepreceding example. Yield, 137 g (61% of theory).

EXAMPLE 7 Preparation of 2-(6-ethylpyridin-2-yl)benzimidazole

2.2 g. of o-phenylenediamine, 3 g. of 6-ethylpicolinic acid and 15 g. ofpolyphosphoric acid were heated at 160°-180° C. under nitrogen gascurrent for 2 hours with stirring. The reaction mixture was diluted with200 ml. of water and neutralized with sodium carbonate. The resultingprecipitate was filtered off, dried, subjected to silica gel columnchromatography (developed with 1:1 by volume mixture of benzene andethyl acetate) and recrystallized from benzene. 3.3 g. of colorlessneedles of the product (74% of theory) was obtained. M.P. 161°-161.5° C.

Analysis, calculated for C₁₄ H₁₃ N₃ : C, 75.31; H, 5.87; N, 18.82.Found: C, 75.52; H, 5.81; N, 18.72.

EXAMPLE 8 Preparation of 2-(5-butylpyridin-2-yl) benzimidazole

0.6 g. of o-phenylenediamine, 1 g. of fusaric acid and 10 g. ofpolyphosphoric acid were heated at 200°-250° C. under nitrogen gascurrent with stirring for 1.5 hours. The reaction mixture was dilutedwith 200 ml. of water and then neutralized with sodium carbonate. Theresulting crystals were filtered off, dried and recrystallized fromethyl acetate. 1.2 g. of colorless needles of the product (86% oftheory) was obtained. M.P. 138.0°-139.0° C.

EXAMPLE 9 Preparation of 2-(2-pyridyl)-5(6)-methylbenzimidazole

18.6 g. of toluylene-3,4-diamine, 18.8 g. of picolinic acid and 120 g.of polyphosphoric acid were heated at 160°-180° C. under nitrogen gascurrent with stirring for 2 hours. The reaction mixture was diluted with1,000 ml. of water and then neutralized with sodium carbonate. Theresulting crystals were filtered off, dried and recrystallized frombenzene. 20 g. (62% of theory) of colorless needles of the product wasobtained. M.P. 164.0°-165.0° C.

EXAMPLE 10 Preparation of2-(5-methylpyridin-2-yl)-5(6)-methylbenzimidazole

2.1 g. of toluylene-3,4-diamine, 2.3 g. of 5-methylpicolinic acid and 15g. of polyphosphoric acid were heated at 200° C. under nitrogen gascurrent with stirring for 2 hours. The reaction mixture was diluted with200 ml. of water and then neutralized with sodium carbonate. Theresulting precipitates were filtered off, dried, subjected to silica gelcolumn chromatography (developed with benzene) and recrystallized fromcyclohexane. 1.3 g. (58% of theory) of colorless needles of the productwas obtained. M.P. 166.5°-167.0° C.

EXAMPLE 11 Preparation of2-(6-methylpyridin-2-yl)-5(6)-methylbenzimidazole

7.0 g. of toluylene-3,4-diamine, 5.4 g. of 2,6-lutidine and 4.8 g. ofsulfur were heated at 160°-170° C. for 5 hours. The reaction mixture wasdissolved in 500 ml. of chloroform. The solution was washed with water,dried and evaporated in vacuo to remove the solvent. The residue wassubjected to silica gel chromatography and recrystallized from 1:1 byvolume mixture of benzene and n-hexane. 7.1 g. (68% of theory) ofcolorless needles of the product was obtined. M.P. 208.0°-209.5° C.

Analysis, calculated for C₁₄ H₁₃ N₃ : C, 75.31; H, 5.87; N, 18.82.Found: C, 75.58; H, 5,85; N, 18.89

EXAMPLE 12 Preparation of2-(5-ethylpyridin-2-yl)-5(6)-methylbenzimidazole

1.2 g. of toluylene-3,4-diamine, 1.5 g. of 5-ethylpicolinic acid and 10g. of polyphosphoric acid were heated at 160°-180° C. under nitrogen gascurrent with stirring for 2 hours. The reaction mixture was diluted with100 ml. of water and then neutralized with sodium carbonate. Theresulting crystals were filtered off, dried, chromatographed throughsilica gel column and recrystallized from cyclohexane. 1.8 g. (77% oftheory) of colorless needles of the product was obtained. M.P.114.0°-115.0° C.

EXAMPLE 13 Preparation of 2-(2-pyridyl)-5(6)-methoxybenzimidazole

11.9 g. of 4-methoxy-o-phenylenediamine hydrochloride, 7 g. of picolinicacid and 40 g. of polyphosphoric acid were heated at 180°-190° C. undernitrogen gas current with stirring for 2 hours.

The reaction mixture was diluted with water and then neutralized withsodium carbonate. The resulting precipitates were filtered off, dried,chromatographed through silica gel column (developed with benzene) andrecrystallized from 1:2 by volume mixture of ethyl acetate and n-hexane.9.0 g. (71% of theory) of colorless needles of the product was obtained.M.P. 136.0°-137.5° C.

EXAMPLE 14 Preparation of2-(5-ethylpyridin-2-yl)-5(6)-methoxybenzimidazole

10.6 g. of 4-methoxy-o-phenylenediamine hydrochloride, 7.6 g. of5-ethylpicolinic acid and 40 g. of polyphosphoric acid were heated at180°-190° C. under nitrogen gas current with stirring for 1 hour. Thereaction mixture was diluted with 500 ml. of water and then neutralizedwith sodium carbonate. The precipitates were filtered off, dried,chromatographed through silica gel column (developed with benzene) andrecrystallized from ligroin. 8.6 g. of colorless needles of the product(67% of theory) was obtained. M.P. 141.5°-142.0° C.

EXAMPLE 15 Preparation of2-(6-methylpyridin-2-yl)-5(6)-methoxybenzimidazole

6.4 g. of 4-methoxy-o-phenylenediamine, 5 g. of 2,6-lutidine and 4.5 g.of sulfur were heated at 150°-160° C. for 1.5 hours.

To the reaction mixture was added 100 ml. of methanol. The precipitatedsulfur was removed by filtering and the filtrate was evaporated invacuo. The residue was chromatographed silica gel column andrecrystallized from benzene. 9.2 g. of colorless needles of the product(82% of theory) was obtained. M.P. 189.0°-191.0° C.

EXAMPLE 16 Preparation of2-(6-ethylpyridin-2-yl)-5(6)-methoxybenzimidazole

2.8 g. of 4-methoxy-o-phenylenediamine hydrochloride, 2.0 g. of6-ethylpicolinic acid and 10 g. of polyphosphoric acid were heated at160°-180° C. under nitrogen gas current with stirring for 2 hours. Thereaction mixture was diluted with 100 ml. of water and then neutralizedwith sodium carbonate. The resulting precipiates were filtered off,chromatographed through silica gel column (developed with 8:2 mixture ofbenzene and ethyl acetate) and recrystallized from n-hexane. 2.4 g. (73%of theory) of colorless needles of the product was obtained. M.P.147.5°-148.5° C.

EXAMPLE 17 Preparation of 2-(2-pyridyl)-5(6)-chlorobenzimidazole

2.5 g. of 4-chloro-o-phenylenediamine, 2.2 g of picolinic acid and 11 g.of polyphosphoric acid were heated at 170°-180° C. under nitrogen gascurrent with stirring for 2 hours. The reaction mixture was diluted with100 ml. of water and then neutralized with sodium carbonate. Theresulting precipitates were filtered off, dried, chromatographed throughsilica gel column (developed with 1:1 mixture of ethyl acetate andbenzene) and recrystallized from cyclohexane. 2.6 g. (65% of theory) ofcolorless needles of the product was obtained. M.P. 141.5°-142.5° C.

EXAMPLE 18 Preparation of2-(5-methylpyridin-2-yl)-5(6)-chlorobenzimidazole

7.8 g. of 4-chloro-o-phenylenediamine, 6.9 g. of 5-methylpicolinic acidand 40 g. of polyphosphoric acid were heated at 170°-180° C. undernitrogen gas current with stirring for 2 hours.

The reaction mixture was diluted with 500 ml. of water and thenneutralized with sodium carbonate. The resulting crystals were filteredoff, dried and recrystallized from benzene. 8.2 g (67% of theory) ofcolorless needles of the product was obtained. M.P. 171.0°-172.0° C.

EXAMPLE 19 Preparation of2-(6-methylpyridin-2-yl)-5(6)-chlorobenzimidazole 7.2 g. of4-chloro-o-phenylenediamine, 5.4 g. of 2,6-lutidine and 4.8 g. of sulfurwere heated at 150°-160° C. with stirring for 6 hours. To the reactionmixture was added 100 ml. of methanol and the separated sulfur wasremoved by filtration. The filtrate was evaporated in vacuo. The residuewas chromatographed through silica gel column and recrystallized frombenzene. 8.9 g. (72% of theory) of cololess needles of the product wasobtained. M.P. 173.5°-174.5° C.

Analysis, calculated for C₁₃ H₁₀ N₃ Cl: C, 64.07; H, 4.14; N, 17.24; Cl,14.55. Found: C, 64.28; H, 4.09; N, 17.30; Cl 14.36.

EXAMPLE 20 Preparation of2-(5-ethylpyridin-2-yl)-5(6)-chlorobenzimidazole

7.2 g. of 4-chloro-o-phenylenediamine, 7.6 g. of 5-ethylpicolinic acidand 40 g. of polyphosphoric acid were heated at 170°-180° C. undernitrogen gas current with stirring for 2 hours.

The reaction mixture was diluted with 500 ml. of water and thenneutralized with sodium carbonate. The resulting precipitates werefiltered off, dried, chromatographed through silica gel column andrecrystallized from cyclohexane. 8.9 g. (70% of theory) of colorlessneedles of the product was obtained. M.P. 169.5°-170.5° C.

EXAMPLE 21 Preparation of 2-(6-ethylpyridin-2-yl)-benzimidazole

1.1 g. of o-phenylenediamine and 1.3 g. of freshly distilled6-cyano-2-ethylpyridine were dissolved in 5 ml. of DMF. To the solutionwas added 0.05 g. of sodium in 1 ml. of methanol. The mixture wasstirred at 60° C. for 30 minutes, then acidified with acetic acid andstirred again at 100° C. for an additional 1 hour. The reaction mixturewas poured in 100 ml. of water. The resulting crystals were filtered offdried and recrystallized from benzene. 1.7 g. (78% of theory) of theproduct was obtained.

This product was identical to the product of Example 7.

EXAMPLE 22 Preparation of 2-(5-ethylpyridin-2-yl)-benzimidazole

1.1 g. of o-phenylenediamine and 1.3 g. of 2-cyano-5-ethylpyridine weredissolved in 5 ml. of methanol. To the solution was added 0.05 g. ofsodium in 1 ml. of methanol. The mixture was refluxed for 2 hours, thenacidified with acetic acid and refluxed again for additional 4 hours.The reaction mixture was evaporated.

The residue was washed with water, dried and recrystallized from ethylacetate. 1.5 g. (72% of theory) of the product which was identical tothe product of Example 5 was obtained.

EXAMPLE 23 Preparation of 2-(p-ethylphenyl) benzimidazole

5.5 g. of o-phenylenediamine, 7.6 g. of p-ethylbenzoic acid and 40 g. ofpolyphosphoric acid were heated at 160°-180° C. under nitrogen gascurrent with stirring for 4 hours. The reaction mixture was diluted with400 ml. of water and then neutralized with sodium carbonate. Theresulting crystals were filtered off, dried and recrystallized fromethyl acetate. 8.2 g. (73% of theory) of the product was obtained. M.P.258°-258.4° C.

In the same way as described, the following compounds were prepared froma corresponding o-phenylenediamine and an appropriately substitutedbenzoic acid:

2-(p-isopropylphenyl) benzimidazole, M.P. 250°-252.5° C.;

2-(p-t-butylphenyl) benzimidazole, M.P. 252.5°-253.5° C.;

2-(o-ethylphenyl)benzimidazole, M.P. 207°-208° C.;

2-(p-ethylphenyl)-5(6)-chlorobenzinidazole, M.P. 199.5°-200.5° C.;

2-(p-ethylphenyl)-5(6)-methylbenzimidazole, M.P. 191.5°-192.5° C.;

2-(m-ethylphenyl)benzimidazole, M.P. 202°-203° C.;

2-(o-ethylphenyl)-5(6)-chlorobenzimidazole, M.P. 183°-184° C.

EXAMPLE 24 Preparation of 2-(p-ethylphenyl)-5(6)-methoxybenzimidazole

8.0 g. of 4-methoxy-o-phenylenediamine hydrochloride, 6.0 g. ofp-ethylbenzoic acid and 40 g. of polyphosphoric ester were heated at120° C. with stirring for 1 hour. The reaction mixture was diluted withwater and then neutralized with sodium carbonate.

The mixture was extracted with ethyl acetate and the extract wasevaporated in vacuo. The resulting crystals were recrystallized fromacetonitrile. 3.4 g. (68% of theory) of the product was obtained. M.P.160°-161° C.

In the same was as described, the following compounds were prepared froma corresponding o-phenylenediamine and an appropriately substitutedbenzoic acid:

2-(o-ethylphenyl)-5(6)-methoxybenzimidazole, M.P. 121°-122° C.;

2-(o-ethylphenyl)-5(6)-methylbenzimidazole, M.P. 166°-166.7° C.

EXAMPLE 25 Preparation of 2-(m-ethylphenyl)benzimidazole

2.2 g. of o-phenylenediamine and 3.1 g. of m-ethylenbenzonitrile weredissolved in 30 ml. of methanol. To the solution was added 1.1 g. ofsodium methoxide in methanol. The mixture was stirred at 60° C. for 2hours, acidified with acetic acid, stirred again at 100° C. foradditional 3 hours and poured in 100 ml. of water. The resultingcrystals were filtered off, dried and recrystallized from ethyl acetate.2.7 g. of the product (60% of theory) was obtained. The product wasidentical to that obtained in Example 23.

EXAMPLE 26 Preparation of 2-(o-ethylphenyl)-5(6)-methylbenzimidazole

5.0 g. of p-toluidine, 6.2 g. of o-ethylbenzonitrile and 6.3 g. ofanhydrous aluminum chloride were heated at 120° C. with stirring for 1hour. To the reaction mixture was added water and sodium hydroxide tomake the mixture alkaline. The mixture was extracted with benzene andthe extract was washed with water, dried and evaporated in vacuo toremove benzene. 10.2 g. (92% of theory) ofN-(p-methylphenyl)-2-ethylbenzamidine was obtained.

5.0 g. of this product was added aqueous methanol and the mixture wasacidified with hydrochloric acid. To the mixture were added an aqueoussolution of sodium hypochlorite until potassium iodide - starch paperturns blue.

The mixture was then made alkaline with sodium carbonate, refluxed for2.5 hours and cooled to room temperature. The resulting crystals werefiltered off, dried and recrystallized from benzene, whereby 3.9 g. (80%of theory) of the product was obtained.

The product was identical to that obtained in Example 24.

EXAMPLE 27 Preparation of 2-(p-ethylphenyl)-5(6)-methoxybenzimidazole

5.0 g. of p-ethylbenzonitrile in 40 ml. of methanolic hydrochloric acidwas stirred at room temperature over night.

The reaction mixture was diluted with water, neutralized with sodiumcarbonate and extracted with n-hexane. The extract was evaporated invacuo to remove n-hexane. The remaining alkoxyimine compound was takenin methanol and 4.7 g. of p-anisidine was added thereto. The mixture waswarmed for 30 minutes and evaporated in vacuo to remove methanol,whereby N-(p-methoxyphenyl)-4-ethylbenzamidine was produced. Thisproduct was dissolved in water and then acidified with hydrochloricacid. To this solution was added an aqueous solution of sodiumhypochlorite until potassium iodide-starch paper turns blue.

The mixture was extracted with methylenechloride. The extract was washedwith water, dried and evaporated at a lower temperature.

The residue was dissolved in 100 ml. of 50% aqueous methanol and 6.0 g.of sodium carbonate in small amount of water was added thereto. Thesolution was refluxed for 1 hour and evaporated in vacuo to removemethanol. The resulting crystals were filtered off, dried andrecrystallized from acetonitrile, whereby 7.0 g. (73% of theory) of theproduct was obtained.

The product was identical to that obtained in Example 24. It is to beunderstood that the foregoing detailed description is given merely byway of illustration and that many variations may be made therein withoutdeparting from the spirit of the present invention.

We claim:
 1. A compound of the formula: ##STR14## wherein R₁ is hydrogen, halogen, C₁ -C₄ alkyl or C₁ -C₄ alkoxy and R₂ is ethyl or tert-butyl.
 2. A compound according to claim 1, 2-(p-tert-butylphenyl)benzimidazole.
 3. A compound according to claim 1, 2-(p-ethyl-phenyl)benzimidazole.
 4. A compound according to claim 1, 2-(m-ethyl-phenyl)-5(6)-methoxy-benzimidazole.
 5. A compound according to claim 1, 2-(o-ethyl-phenyl)-5(6)-methoxy-benzimidazole.
 6. A compound according to claim 1, 2-(m-ethyl-phenyl)benzimidazole.
 7. A pharmaceutical composition for use in treating inflammation comprising an anti-inflammatory effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable carrier.
 8. A pharmaceutical composition according to claim 7, wherein said compound is 2-(p-tert-butylphenyl) benzimidazole.
 9. A pharmaceutical composition according to claim 7, wherein said compound is 2-(p-ethylphenyl) benzimidazole.
 10. A pharmaceutical composition according to claim 7, wherein said compound is 2-(m-ethylphenyl) benzimidazole.
 11. A pharmaceutical composition according to claim 7, wherein said compound is 2-(o-ethylphenyl)-5 (6)-benzimidazole.
 12. A pharmaceutical composition according to claim 7, wherein said compound is 2-(m-ethylphenyl)-5 (6)-benzimidazole. 